Dr. Scott M. Palmer, currently on faculty in the Duke University Pulmonary Division as an Associate in Medicine, proposes a structured five-year career development plan in order to develop into an independent investigator in pulmonary medicine. The proposal involves rigorous research training under an experienced physician scientist mentor, Dr. David Schwartz, who has expertise in the immunogenetics of innate immunity. Further research training is proposed under the guidance of a co-mentor with expertise in statistical genetics, a collaborator with expertise in transplant immunology, and complemented by didactic graduate coursework. The overall goal of the proposed research is to understand how innate immune responses contribute to the development of posttransplant bronchiolitis obliterans syndrome (BOS). We hypothesize that genetic, physiological or biological differences in innate immune responsiveness will significantly alter the risk for the development of BOS after lung transplant. This novel hypothesis is clinically relevant based on the high rate of posttransplant death due to BOS, scientifically relevant because of the incomplete understanding of the pathophysiology of BOS, and supported by several basic and clinical observations. We and others have recently demonstrated that significant polymorphisms exist in innate immune receptor genes, and that these differences significantly alter subsequent inflammatory and immune responses. In order to test our hypothesis, we will characterize polymorphisms in donor and recipient toll-like receptor-2 (TLR2), TLR4, and CD14 genes, and phenotypically characterize the airway physiological and biological response to endotoxin in a cohort of 120 lung transplant recipients. We will prospectively capture clinical information on the cohort and determine the predictive importance of innate genetic, physiological, or biological factors on the development or progression of BOS in a multivariate model. At the conclusion of the career development award, Dr. Palmer will have gained considerable expertise in study design, basic genetic analyses, transplant immunology, and statistical analyses. He will apply these skills to direct future investigations of patient oriented research problems in pulmonary medicine.